ProjectSummary/Abstract Lungcanceristhoughttodevelopinastepwisefashiongivingustheopportunitytointervenebeforeitbecomes invasive.Anovelapproachtocurepatientsoflungcanceristhereforetodevelopatargetedchemoprevention strategytopreventtheformationoflungpremalignantlesionsinthefirstplace.Mylabstudiesairwaybasalstem cells(ABSCs)andthesignalingpathwaysinvolvedintheirrepairandregenerationafterinjury.Ourstudiesled ustotheconclusionthatpremalignancyrepresentsastateofexcessiveself-renewalofABSCswithablockin differentiation and we identified several mechanisms involved in stepwise progression to Squamous Lung Cancer.OnesuchmechanisminvolvesproliferationofABSCsviatheWnt-?-cateninpathwayandinparticular wefoundthatonlyoneofthedifferentialphosphorylationsites,thetyrosineY489residueofthe?-cateninprotein, allowed nuclear localization of ?-catenin with concomitant TCF/LEF activation for proliferation. We found that phosphorylation of other classically described ?-catenin phosphorylation sites only resulted in membranous localizationof?-catenin.Thephosphorylationof?-cateninatY489(p-?-cateninY489)isnotpresentinnormal airwayABSCsandisturnedononlybrieflyduringnormalrepairafterinjury,butitpersistsinpremalignantlesion ABSCsandinasubsetofcellsinSquamousLungCancer(SLC). Our goal is to understand the mechanisms that drive phosphorylation of ?-catenin at Y489 and discover compoundstopreventthisprocess.Thiswillallowustopreventtheexcessiveproliferationofpremalignancy anddevelopanovelchemopreventionstrategyforSLC.Wewillachievethisgoalwiththefollowingaims: SpecificAim1:Tounderstandtheroleofp-?-cateninY489inproliferationofABSCs,premalignantlesionsand lungcancers.Wehypothesizethatp-?-cateninY489isacommonmechanismforproliferationinallhistologic subtypesoflungcancer. Specific Aim 2: To identify the kinase/s responsible for phosphorylation of ?-cateninY489 site in ABSCs. We hypothesize that there are specific kinase/s that phosphorylate ?-catenin at the Y489 site which drives proliferationofABSCstoformpremalignantlesions. Specific Aim 3: To identify compounds that prevent p-?-cateninY489. We will perform a targeted screen of compoundsthatpreventTCF/LEFactivationinABSCsalongwithatoxicityscreen.Thiswillallowustoidentify compoundsthatinhibitproliferationbutarenottoxictoABSCs.Leadcompoundsfromthisprimaryscreenwill betakentoasecondaryscreenwithimmunofluorescenceforp-?-cateninY489. Ourhighlyaccomplishedresearchteam,theoutstandingenvironmentatUCLAandtheimportantbiologythatis being addressed in this proposal all provide a high likelihood that this NCI Provocative Question 1 will be answeredfortargetingpremalignancyinNon-SmallCellLungCancerandleadtothedevelopmentofatargeted chemopreventionstrategyforLungCancerthatwillsavemillionsoflives.